Neonatal dietary gangliosides

Early Human Development 53 Suppl. (1998) S135–S147

Neonatal dietary gangliosides

a , b b c* ´Ricardo Rueda , Jose Maldonado , Eduardo Narbona , Angel GilaResearch and Development Department, Abbott Laboratories, Granada, Spain

bDepartment of Pediatrics, School of Medicine, University of Granada, Granada, SpaincDepartment of Biochemistry and Molecular Biology, School of Pharmacy, University of Granada,

Granada, Spain

Abstract

Gangliosides are glycosphingolipis that are widely distributed in vertebrate tissues and bodyfluids and which are specially abundant in neural tissues. Milk from different species has aparticular ganglioside content and profile. Human milk has a higher content of gangliosidesthan bovine milk. GD and GM are the predominant individual gangliosides in bovine milk.3 3

In human colostrum GD is also the main ganglioside whereas in human mature milk GM3 3

predominates over the other gangliosides. Human milk also contains GM and a number of1

highly polar gangliosides, which may play an important role in infant physiology. GM has1

been shown to inhibit Escherichia coli and Vibrio cholerae enterotoxins. We have found that aganglioside-supplemented infant formula modifies the intestinal ecology of preterm newborns,increasing the Bifidobacteria content and lowering that of Escherichia coli. Although the exactmechanism by which dietary gangliosides reduce the fecal content of Escherichia coli isunknown, in vitro experiments suggest that they may act as false intestinal receptors for somestrains of this bacteria. Since GD and other gangliosides have been involved in mechanisms of3

lymphocyte activation and differentiation, dietary gangliosides might have a function inintestinal immunity development. 1998 Elsevier Science Ireland Ltd. All rights reserved.

Keywords: Gangliosides; Human milk; Bovine milk; Infant Formula; Lactation; Newborn

1. Introduction

Gangliosides are glycosphingolipids consisting of a hydrophobic ceramide and ahydrophilic oligosaccharide chain bearing one or more sialic-acid residues in additionto a number of sugars, namely glucose, galactose, N-acetylglucosamine and N-acetylgalactosamine [56]. Ceramide is an N-acylsphingosine in which the acyl residue

*Corresponding author. Tel.: 1 34-58-248651; fax: 1 34-58-248660.

0378-3782/98/$ – see front matter 1998 Elsevier Science Ireland Ltd. All rights reserved.PI I : S0378-3782( 98 )00071-1

S136 R. Rueda et al. / Early Human Development 53 Suppl. (1998) S135 –S147

is usually a saturated fatty acid. Although gangliosides were first detected in thebrain, it is possible to find them in almost all vertebrate tissues and body fluids [58].

The nomenclature developed by Svennerholm [50] continues to be the mostcommonly used because of its rationality, simplicity, and ease of remembering. Theletter G is common to all gangliosides; this letter is followed by one of the next latinletter initials: M, D, T, Q, P, H or S, corresponding to one, two, three, four, five, orexceptionally, six or seven sialic-acid residues present in the molecule. Thus, they arecalled monosialogangliosides, disialogangliosides, trisialogangliosides, etc,... The twoletters are followed by a subindex figure corresponding to a different number of sugarresidues in the oligosaccharide moiety (1: four residues; 2: three residues; 3: tworesidues, and 4: one residue). An additional subindex letter (a, b, c, d) indicates thepathway by which the molecule was biosynthetized. Thus, the abbreviation GD1b

corresponds to a disialoganglioside different from GD by the position of the two1a

sialic-acid residues within the molecule.The Nomenclature Commission of the International Union of Biochemistry has

established a more detailed but more complex ganglioside nomenclature [57]. Theposition of the sugar residue with respect to the ceramide is indicated by a romannumber (I to IV) and the position of the bond of the first sugar with the following

Table 1Ganglioside nomenclature

Svennerholm IUB3GM I aNeuAc-GalCer43GM I aNeuAc-GlcCer4

3GM II aNeuAc-LacCer33GM II aNeuGc-LacCer33GD II a(NeuAc) -LacCer3 23GD II a(NeuGc) -LacCer3 23GD II a(NeuAc, NeuGc)-LacCer33GM II aNeuAc-GqOsa Cer2 33GD II a(NeuAc) -GqOsa Cer2 2 33GM II aNeuAc-GqOsa Cer1 4

3LM IV aNeuAc-nLcOsa Cer1 43– IV aNeuGc-nLcOsa Cer4

3 3GD II aNeuAc IV NeuAc-GqOsa Cer1a 43GD II a(NeuAc) Cer1b 2

3LD IV (NeuAc) -nLcOsa Cer1 2 43 3GT IV (NeuAc) II NeuAc-GqOsa Cer1a 2 43 3GT IV NeuAc, II (NeuAc) -GqOsa Cer1b 2 4

3GT II (NeuAc) -GqOsa Cer1c 3 43 3GQ IV (NeuAc) , II (NeuAc) -GqOsa Cer1b 2 2 43 3GQ IV NeuAc II (NeuAc) -GqOsa Cer1c 2 43 3GP IV (NeuAc) II (NeuAc) -GqOsa Cer1b 3 2 43 3GP IV (NeuAc) II (NeuAc) -GqOsa1c 2 3 4Cer3– VI NeuAc-nLcOsa Cer6

IUB, International Union of Biochemistry.

R. Rueda et al. / Early Human Development 53 Suppl. (1998) S135 –S147 S137

residue is indicated by an exponent of the roman number in arabics. Table 1 showsthe nomenclature and names of the most well known gangliosides.

Variations in sialic-acid structures also contribute to the diversity in gangliosides.The sialic-acid residues in gangliosides are present either as N-acetyl-neuraminic acid(NeuAc) or N-glycolyl-neuraminic acid (NeuGc). Occasionally, both types of sialicacid are present in the same structure.

2. Localization and biological functions of gangliosides

Gangliosides are widely distributed in most vertebrate tissues. Within each speciesthe ganglioside profile may vary from one tissue to another and this could be relatedto a different function for each individual ganglioside.

Gangliosides are specially abundant in neural tissues. Cerebral grey matter containsconsiderably higher concentrations of gangliosides than does white matter orperipheral nervous tissues. The major gangliosides in the brain of higher vertebratesare GM , GD , GD , and GT , which account for 80–90% of the total1 1a 1b 1b

gangliosides [1]. Primate and avian species possess an additional ganglioside, GM ,4

which is particularly abundant in white matter [58].Gangliosides are preferentially located in the surface of cell membranes with the

hydrophylic portion oriented to the outward cell environment. In the nervous system,gangliosides are constituents of the synaptic plasma membranes and synaptic vesicles[23]. There have also been several reports on the soluble cytosolic pool ofgangliosides in mammalian brains although the concentration in this pool isextremely low [58].

Gangliosides have also been isolated from skeletal and smooth muscles [6,27],liver [41], pancreas [28], spleen [30,31], placenta [24,54], thymocytes [32], lympho-cytes [12,33,59], erythrocytes [25], plasma [20], amniotic fluid [42] and milk [17].GD and GD have also been reported as differentiation markers for T 2 and T 11a 1a H H

lymphocyte subpopulations, respectively [7].Cell behaviour, comprising cell communication, growth and differentiation regula-

tion, programmed cell death, immune response, and perhaps the development ofmalign tumors, is mediated mainly by the cell surface and more specifically bybranched-chain sugar molecules universally present in plasma-cell membranes [48].These functions are mainly carried out by sphingolipids. The current paradigm fortheir action is that complex sphingolipids such as gangliosides interact with growth-factor receptors, the extracellular matrix, and neighbouring cells, whereas thebackbone sphingosine and other long-chain or sphingoid bases, ceramides, andsphingosine 1-phosphate, activate or inhibit protein kinases or phosphatases, iontransporters, and other regulatory machinery [49].

Recent studies suggest that gangliosides could be involved in the activation of Tcells [59] and in the differentiation of different lymphocyte subpopulations[7,28,29,51]. Likewise, gangliosides have also been involved as receptors fordifferent bacteria and toxins [22,60].


3. Milk gangliosides

Milk gangliosides are almost exclusively associated with the membrane fraction ofthe fat globule, which is derived mainly from the apical plasma membrane of theapocrine secretory cells in the lactating mammary gland [18,19].

3.1. Bovine-milk gangliosides

Milk gangliosides were initially studied in bovine milk. The sialic-acids ofbovine-milk gangliosides include both NeuAc and NeuGc [5]. In most studies, GD3

was the major ganglioside of cow milk, and GM was the next most abundant. Other3

gangliosides amounted to no more than 20% of the total ganglioside content. Huang[11] found that bovine buttermilk is a rich source of gangliosides, GD and GM3 3

being the principal individual gangliosides. GD comprises 85% of the total3

gangliosides of buttermilk [10].Takamizawa et al. [52] reported that buttermilk contains 0.92 mmol of LBSA per

gram of dry weight, 80% of which is in the form of GM , GD , and GT . Other3 3 3

authors have also reported the existence of acetylated gangliosides in buttermilk[4,40].

During recent years, several works have shown the existence of variations in theganglioside content and individual distribution in colostrum, transitional, and maturebovine milk. Puente et al. [35] found in Spanish-Brown cows that the gangliosidecontent was higher in colostrum (7.5 mg of LBSA/kg) than in transitional (2.3 mg)or mature milk (1.4 mg). The sialic-acid content followed a profile similar to that ofgangliosides with the highest content during the immediate postnatal days, followedby a gradual decrease towards the end of lactation. Several changes were also foundwhen the individual distribution of gangliosides was examined. GM , GD , and GT3 3 3

accounted for 80–90% of the total ganglioside content, GD being the major single3

component (60–70%). GM increased from the first to the fifth day, whereas GD3 3

decreased during this period. However, GD increased from day 5 to the end of3

lactation, as GM decreased. Lactational changes in the NeuGc content of bovine3

milk gangliosides have also been described [36]. The NeuGc content of gangliosides,as well as that in total sialic-acids, was high in colostrum and decreased thereafteruntil the end of lactation.

Ganglioside and sialic-acid contents of goat milk also change during lactation [37].The highest ganglioside content appeared in colostrum (974 mg LBSA/kg) and thendecreased to the end of lactation (175 mg LBSA/kg). The sialic-acid contentexhibited a trend similar to that of gangliosides; during early lactation sialic-acidcontent (1147 mg/kg) was higher than in mature milk (203 mg/kg). As in cow milk,GM , GD , and GT were the most abundant individual gangliosides (66 to 92%).3 3 3

Likewise, the content of GM decreased whereas that of GD increased during3 3

lactation.The ganglioside content of sheep milk varied during lactation in a similar way to

that of cow and goat milk, being high at the beginning of lactation and decreasingthereafter [38]. Sheep milk had half the amount of gangliosides (expressed as LBSA)


detected in goat milk, and 6–7% of the ganglioside content of cow milk. Thesialic-acid content of sheep milk followed a trend similar to that of gangliosides,being higher in early lactation than in mature milk.

Seasonal variations in the concentration of gangliosides have also been described inmilk from different mammalian species [39]. All species considered showed thehighest ganglioside content in autumn, whereas the minimum ganglioside content wasobserved in summer milk for cows and goats but not for sheep.

3.2. Human-milk gangliosides

The content and distribution of gangliosides in human milk have been reported byseveral authors [21,22,53]. Table 2 summarizes these earlier findings and our ownresults [43].

The ganglioside levels detected by Takamizawa and colleagues [53] were slightlyhigher than those detected by us. However, this group did not study any samplebetween 14 and 40 days, and we detected a significant increase in the gangliosideconcentration in human milk during this period of lactation, specially between 14 and21 days, 17 day showing the highest value (11.93 mg LBSA/g fresh milk).

We also quantified the total lipid content of our milk samples and found asignificant positive correlation between ganglioside and total lipid contents [43].Although this correlation was not strong, the increase in total lipid content in humanmilk during mid-lactation [16] may explain why we detected higher concentrations ofgangliosides and total lipids in our samples from the third week of lactation.

Like Takamizawa et al. [53], we observed a selective change in the relativeconcentrations of GM and GD between colostrum (days 1–5) and mature milk. The3 3

most abundant ganglioside in human milk at the beginning of lactation was GD ,3

whereas, at the end of this period, GM was the major ganglioside (Fig. 1).3

A major finding in our studies was the detection of previously unreported highlypolar gangliosides in human milk (Fig. 1). Their high polarity suggests that they maybe polysialogangliosides or complex gangliosides with branched oligosaccharidechains. Neither of these compounds has been found in earlier studies of milkgangliosides. These structurally complex gangliosides may play an important role,within the mammary gland and in developing neonatal tissues, especially at thebeginning of lactation.

We studied the changes in the relative concentration of individual gangliosides inhuman milk from mothers delivering preterm and term infants during lactation [44].The relative content of GD was higher in colostrum than in mature milk, and tended3

to be higher in preterm than in term colostrum, whereas the relative content of GM3

was higher in mature milk than in colostrum, and was also higher in term than inpreterm milk. As GD is usually detected in developing tissues whereas GM is more3 3

abundant in mature tissues [58], these results suggest a relationship between thepresence of individual gangliosides in human milk and immaturity of the mammarygland in mothers of preterm infants.

Lactational changes in content and distribution of gangliosides in human milk fromSpanish and Panamanian mothers delivering at term newborns have also been studied

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Table 2Previously published data on the content and distribution of human milk gangliosides

Reference Human milk samples Ganglioside content Ganglioside distribution

Laegreid A et al, 1986 Pooled milk samples 11 mg/ l fresh milk Monosialoganglioside(Pediatr Res 20, from 2 to 10 months (74%) and disialogan-416–421) postpartum glioside (25%)Laegreid A et al, 1986 Pooled milk samples 0.33 mg/g dry milk fat G 1 G ( . 95%), andM3 D3

(J Chromatography from 2 to 10 months traces of a monosialo-377:59–67) postpartum ganglioside close to GM2

Takamizawa K et al, Individual milk samples Changes during lactation Changes in G and GM3 D3

1986 (Biochim Biophys from 2 to 390 days (Range: 2.34 to 1.01 mmol concentration duringActa 879:73–77) postpartum LBSA/100 ml fresh milk) lactationRueda R et al, 1995 Individual milk samples Changes during lactation Changes in G and GM3 D3

(Biol. Chem, Hoppe from 1 to 150 days (Range: 11.93 to 0.82 concentration duringSeyler 376; 723–727) postpartum mg LBSA/g fresh milk) lactation

Significant correlation Presence of previously(r 5 0.5564; P 5 0.0165) unreported highly polarbetween ganglioside and gangliosides in humantotal lipid contents in milk, and changes inhuman milk their concentration

during lactation


Fig. 1. high-performance thin-layer chromatography (HPTLC) of human milk gangliosides. Lanes a:Standard gangliosides from pig brain; b: Human milk gangliosides at 4 days of lactation; c: Human milkgangliosides at 8 days of lactation; d: Human milk gangliosides at 90 days of lactation. G1 5 GM3;G3 5 GD3; G5–G8 5 Polar Gangliosides.

by our group to test the influences of different ethnic populations, dietary habits andway of life [45]. There were no statistically significant differences in the con-centration of gangliosides between Spanish and Panamanian milk. Gangliosidecontent expressed as a function of total milk lipids tended to decrease as lactationprogressed in both types of milk. There was a significant correlation between theganglioside and total lipid contents in Panamanian milk. However, in Spanish milk,that correlation was not significant. We did not detect important differences in therelative concentration of individual gangliosides during lactation between milk fromSpanish and Panamanian mothers. For both of them, GD was the most abundant3

ganglioside in colostrum, whilst in mature milk it was GM .3

4. Nutritional roles of gangliosides

Human and bovine milk present a different content and distribution of gangliosides[21]. Since cow milk is used to manufacture infant formulas, their gangliosidedistribution is similar, although the absolute content is lower in formulas than in cowmilk. Nevertheless, the content of gangliosides in human milk is higher than that


found in milk formulas. According to this feature, and taking into account thepotential role of human milk gangliosides, the supplementation of infant formulaswith those molecules could be of importance in neonatal physiology.

The role of gangliosides in human milk has not been established. A highconcentration of GD has been detected in developing tissues [2]. A high con-3

centration of GD has also been detected in human colostrum and this may therefore3

reflect a biological role in the development of organs such as the intestine in theneonate. However, biological studies on growth and differentiation of intestinal cellsin the presence of gangliosides will be needed to test this hypothesis. As wementioned above, human milk contains a significant amount of highly polargangliosides [43]. This type of gangliosides has been detected in developing tissues[3,34] and biological fluids [42]. The function of these highly complex gangliosidesin developing tissues is unknown, but it has been suggested that they act as mediatorsof specific types of cell contact interactions during the early stages of mammaliandevelopment [9]. Thus, the complex gangliosides in human milk may be shed by thelactating mammary gland, and may play an important role in this organ or indeveloping infant tissues, particularly the small intestine, during early life. Charac-teristic expression of GD during lactation in murine mammary gland with a parallel1a

concentration in the milk fat globule has been described [26].Human milk gangliosides have also been implicated in the inhibition of Es-

cherichia coli and Vibrio cholerae enterotoxins. This inhibitory action has beenattributed to the monosialoganglioside GM , which has been identified as the receptor1

for these enterotoxins [21,22]. More recently, siayllactose has been identified as themoiety responsible for the inhibitory activity of milk on cholera toxin [15]. GM is1

found in human milk only in very low concentrations, and immunological methodsare necessary to detect it on HPTLC plates [22]. However, the concentration of GM1

is 10 times higher in human than in bovine milk [21]. All these findings suggest thatgangliosides play an important role as false receptors in the defense against infectionduring lactation.

We have found that the addition to an adapted milk formula of gangliosides at aconcentration similar to that in human milk modifies the microbial composition offeces of preterm newborn infants. The fecal E. coli counts in preterm infants fed theganglioside supplemented formula were lower than those observed in infants fed thestandard formula for the first month of life (Fig. 2); conversely, the fecal counts ofBifidobacteria in the group having the ganglioside formula were higher, especially at30 days of postnatal age (Fig. 2) [46].

Although the exact mechanism by which dietary gangliosides reduce the fecallevels of Escherichia coli is unknown, in vitro experiments suggest that gangliosidesinteract with specific Escherichia coli strains [8]. Gangliosides have been reported ascalf and pig small intestine receptors for K99 fimbriated enterotoxigenic E. coli [55].The inhibitory effects of human milk gangliosides and their derivatives on theadhesion of enterotoxigenic and enteropathogenic Escherichia coli to Caco-2 cells, ahuman intestinal carcinoma cell line, have been recently published [14]. Likewise, themeconium and feces of breast-fed newborns have been reported to inhibit theadhesion of S-fimbriated Escherichia coli to epithelial cells [47]. The stronger


Fig. 2. (a) Logarithmic Escherichia coli counts in feces of preterm newborn infants fed on milk formula(MF) and ganglioside-supplemented milk formula (GMF). Results are means6SEM. Twenty samples wereanlayzed for each feeding group. Samples were collected at 3, 7 and 30 days of life. Kruskal Wallisnonparametric test was used to determine the effect of the diet as source of variation. s P , 0.01; d

P , 0.001 respect to MF. (b) Logarithmic bifidobacteria counts in feces of preterm newborn infants fed onmilk formula (MF) and ganglioside-supplemented milk formula (GMF). Results are means6SEM. Twentysamples were anlayzed for each feeding group. Samples were collected at 3, 7 and 30 days of life. KruskalWallis nonparametric test was used to determine the effect of the diet as source of variation. s P , 0.05respect to MF.


inhibitory capacity found in meconium has been linked to the concentration of sialicacid. It was recently shown that meconium gangliosides are oncofetal gangliosides,and their structure resembles that of some human milk oligosaccharides and somebuttermilk gangliosides [54].

These data suggest that sialyloligosaccharides and other compounds with conju-gated sialylated carbohydrates (glycoproteins and glycolipids) could function asreceptor-analogous structures for bacterial adhesins. Such compounds could modifythe intestinal microflora in the neonate and reduce the infectious capacity of thesebacteria.

Our recent data [46] suggests that colonization of bifidobacteria flora is faster ininfants fed with a milk formula supplemented with gangliosides. These compoundswhich are present in human milk but practically absent from milk formula, may beone of the components that promote the growth of bifidobacteria. In fact, it has beenrecently reported that fortification with N-acetylneuraminic acid-containing sub-stances of infant formula may provide formula-fed infants with a function that humanmilk possesses, that is the growth-promoting effect on bifidobacteria [13]. The highcontent of sialic acid in breast-fed infants probably also contributes to the lowintestinal pH, which in turn favours bifidobacterial flora.

In conclusion, ganglioside-supplemented milk formulas may promote the growth ofbifidobacteria and suppress the growth of Escherichia coli and possibly otherpotentially pathogenic microorganisms in the intestine of preterm newborn infants.However, further studies are required to clarify the mechanisms implicated in thisaction and the relevance of this finding to clinical outcome in preterm neonates. AsGD is one of the most important gangliosides in human milk and it has been recently3

involved in the mechanism of activation of T lymphocytes, the supplementation ofmilk formulas with this ganglioside might play an important role in the process ofproliferation, activation, and differentiation of intestinal immune cells in the neonate.

References

[1] Ando S, Chang NC, Yu RK. High-performance thin-layer chromatography and densitometricdetermination of brain ganglioside composition of several species. Anal Biochem 1978;89:437–50.

[2] Ando S. Gangliosides in the nervous system. Neurochem Int 1983;5:507–37.[3] Asano K, Suzuki M, Handa S, Oshima M. Acidic glycosphingolipids of human amnion. J Biochem

1991;109:106–12.[4] Bonafede DM, Macala LJ, Constantine-Paton M, Yu RK. Isolation and characterization of ganglioside

9-O-Acetyl-GD3 from bovine buttermilk. Lipids 1989;24:680–4.[5] Bushway AA, Keenan TW. Composition and synthesis of three higher ganglioside analogs in bovine

mammary tissue. Lipids 1978;13:59–65.[6] Dasgupta S, Chien JL, Hogan EL, van Halbeek H. A disialoganglioside of the globo series from

chicken skeletal muscle. J Lipid Res 1991;32:499–506.¨[7] Ebel F, Scmitt E, Peter-Katalinic J, Kniep B, Muhlradt PF. Gangliosides: differentiation markers for

murine T helper lymphocyte subpopulations TH1 and TH2. Biochemistry 1992;31:12190–7.[8] Ettinger AC. US Patent, 4, 762, 822. 1988.[9] Friedman SJ, Cheng S, Skehan P. The occurrence of polysialogangliosides in a human trophoblast cell

line. FEBS Lett 1983;152:175–9.


[10] Hauttecoeur B, Sonnino S, Ghidoni R. Characterization of two molecular species G gangliosideD3

from bovine buttermilk. Biochim Biophys Acta 1985;833:303–7.[11] Huang RTC. Isolation and characterization of the gangliosides of buttermilk. Biochim Biophys Acta

1973;306:82–4.[12] Hueso P, Reglero A, Rodrigo M, Cabezas JA. Isolation and characterization of gangliosides from pig

lymphocytes. Biol Chem Hoppe-Seyler 1985;366:167–71.[13] Idota T, Kawakami H, Nakajima I. Growth-promoting effects of n-acetylneuraminic acid-containing

substances on bifidobacteria. Biosci Biotech Biochem 1994;58:1720–2.[14] Idota T, Kawakami H. Inhibitory effects of milk gangliosides on the adhesion of escherichia coli to

human intestinal carcinoma cells. Biosci Biotech Biochem 1995;59:69–72.[15] Idota T, Kawakami H, Murakami Y, Sugawara M. Inhibition of cholera toxin by human milk fractions

and sialyllactose. Biosci Biotech Biochem 1995;59:417–9.[16] Jensen RG. The lipids of human milk. Boca Raton: CRC Press, 1989.[17] Jensen RG, Newburg DS. Bovine milk lipids. In: Jensen RG, editor. Handbook of Milk Composition.

New York: Academic Press, 1995:543–75.[18] Keenan TW, Huang CM, Moore DJ. Gangliosides: non-specific localization in the surface membranes

of bovine mammary gland and rat liver. Biochim Biophys Res Commun 1972;47:1277–83.[19] Keenan TW. Composition and synthesis of gangliosides in mammary gland and milk of the bovine.

Biochim Biophys Acta 1974;337:255–70.[20] Ladisch S, Gillard B. Isolation and purification of gangliosides from plasma. Methods Enzymol

1987;138:300–6.[21] Laegreid A, Otnaess ABK, Fuglesang J. Human and bovine milk: comparison of ganglioside

composition and enterotoxin-inhibitory activity. Pediatr Res 1986;20:416–21.[22] Laegreid A, Otnaess ABK. Trace amounts of ganglioside GM1 in human milk inhibits enterotoxin

from vibrio cholerae and escherichia coli. Life Sci 1987;40:55–62.[23] Leeden RW. Biosynthesis, metabolism, and biological effects of gangliosides. In: Margolis RU,

Margolis RK, editors. Neurobiology of Glycoconjugates. New York: Plenum Press, 1989.[24] Levery SB, Nudelman ED, Salyan MEK, Hakomori S-i. Novel tri- and tetrasialosylpoly-n-acetyllac-

tosaminyl gangliosides of human placenta: structure determination of pentadeca- andeicosaglycosylceramides by methylation analysis, fast atom bombardement mass spectrometry, and1H NMR spectroscopy. Biochemistry 1989;28:7772–81.

[25] Miller-Podraza H. Complex gangliosides of bovine erythrocytes. Biochem Biophys Acta1989;586:209–12.

[26] Momoeda M, Momoeda K, Takamizawa K, et al. Characteristic expression of GD1 alpha gangliosideduring lactation in murine mammary gland. Biochim Biophys Acta 1995;1256:151–6.

[27] Mukhin DN, Prokazova NV, Bergelson LD, Orekhov AN. Ganglioside content and composition ofcells from normal and atherosclerotic human aorta. Atherosclerosis 1989;78:39–45.

[28] Nakamura K, Suzuki H, Hirabayashi Y, Suzuki A. IV alpha (NeuGc alpha 2-8NeuGc)-Gg4Cer isrestricted to CD4 1 T cells producing interleukin-2 and a small population of mature thymocytes inmice. J Biol Chem 1995;270:3876–81.

[29] Nashar TO, Webb HM, Eaglestone S, Williams NA, Hirst TR. Potent immunogenicity of the Bsubunit of escherichia coli heat-labile enterotoxin: receptor binding is essential and inducesdifferential modulation of lymphocyte subsets. Proc Natl Acad Sci USA 1996;93:226–30.

[30] Nohara K, Suzuki M, Inagaki F, Ito H, Kaya K. A unique fucoganglioside with blood group Bdeterminant in rat spleen. J Biochem 1990;108:684–8.

[31] Nohara K, Suzuki M, Inagaki F, Ito H, Kaya K. Identification of novel gangliosides containinglactosaminyl-GM structure from rat spleen. J Biol Chem 1990;265:14335–9.1

[32] Nohara K, Suzuki M, Inagaki F, Kaya K. A GM -derived disialoganglioside GD1c Is the1b

predominant ganglioside of rat thymocytes. J Biochem 1991;110:274–8.[33] Nohara K, Nakauchi H, Spiegel S. Glycosphingolipids of rat T cells. Predominance of asialo-GM1

and GD1c. Biochemistry 1994;33:4661–6.[34] Nudelman ED, Mandel U, Levery SB, Kaizu T, Hakomori S. A series of disialogangliosides with

binary 2–3 sialosyllactosamine structure, defined by monoclonal antibody NUH2. Are oncodevelop-mentally regulated antigens. J Biol Chem 1989;264:18719–25.


´[35] Puente R, Garcıa-Pardo LA, Hueso P. Gangliosides in bovine milk. Changes in content anddistribution of individual ganglioside levels during lactation. Biol Chem Hoppe-Seyler 1992;373:283–8.

[36] Puente R, Hueso P. Lactational changes in the N-glycolylneuraminic acid content of bovine milkgangliosides. Biol Chem Hoppe-Seyler 1993;374:475–8.

´[37] Puente R, Garcıa-Pardo LA, Rueda R, Gil A, Hueso P. Changes in ganglioside and sialic acidcontents of goat milk during lactation. J Dairy Sci 1994;77:39–44.

´[38] Puente R, Garcıa-Pardo LA, Rueda R, Gil A, Hueso P. Ewes’ milk: changes in the contents ofganglioside and sialic acid during lactation. J Dairy Res 1995;62:651–4.

´[39] Puente R, Garcıa-Pardo LA, Rueda R, Gil A, Hueso P. Seasonal variations in the concentration ofgangliosides and sialic acids in milk from different mammalian species. Int Dairy J 1996;6:315–22.

[40] Ren S, Scarsdale JN, Ariga T, et al. O-acetylated gangliosides in bovine buttermilk. J Biol Chem1992;267:12632–83.

[41] Riboni L, Ghidoni R, Benevento A, Tettamanti G. Content, pattern and metabolic processing of ratliver gangliosides during liver regeneration. Eur J Biochem 1990;194:377–82.

[42] Rueda R, Tabsh K, Ladisch S. Detection of complex gangliosides in human amniotic fluid. FEBS Lett1993;328:13–6.

[43] Rueda R, Puente R, Hueso P, Maldonado J, Gil A. New data on content and distribution ofgangliosides in human milk. Biol Chem Hoppe-Seyler 1995;376:723–7.

´ ´[44] Rueda R, Garcıa-Salmeron JL, Maldonado J, Gil A. Changes during lactation in gangliosidedistribution in human milk from mothers delivering preterm and term infants. Biol Chem1996;377:599–601.

[45] Rueda R, Maldonado J, Gil A. Comparison of content and distribution of human milk gangliosidesfrom Spanish and Panamanian mothers. Ann Nutr Metabolism 1996;40:194–201.

´ ´[46] Rueda R, Sabatel JL, Maldonado J, Narbona E, Gil A. La suplementacion de una formula infantil˜´ ´ ´adaptada con gangliosidos modifica la microflora fecal en ninos recien nacidos pretermino. Madrid: I

Congreso Nacional SENBA, 1996.[47] Schroten H, Lethen A, Hanisch FG, et al. Inhibition of adhesion of S-fimbriated escherichia coli to

epithelial cells by meconium and feces of breast-fed and formula-fed newborns: mucins are the majorinhibitory component. J Pediatr Gastroenterol Nutr 1992;15:150–8.

[48] Sharon N, Lis H. Lectins as cell recognition molecules. Science 1989;246:227–34.[49] Spiegel S, Merril Jr. AH. Sphingolipid metabolism and cell growth regulation. FASEB J

1996;10:1388–97.[50] Svennerholm L. Chromatographic separation of human brain gangliosides. J Neurochem

1963;10:613–23.[51] Taga S, Tetaud C, Mangeney M, Tursz T, Wiels J. Sequential changes in glycolipid expression during

human B cell differentiation: enzymatic basis. Biochim Biophys Acta 1995;1254:56–65.[52] Takamizawa K, Iwamori M, Mutai M, Nagai Y. Gangliosides of bovine buttermilk. Isolation and

characterization of a novel monosialoganglioside with a new branching structure. J Biol Chem1986;261:5625–30.

[53] Takamizawa K, Iwamori M, Mutai M, Nagai Y. Selective changes in ganglioside of human milkduring lactation: a molecular indicator for the period of lactation. Biochim Biophys Acta1986;879:73–7.

[54] Taki T, Rokukawa C, Kasama T, et al. Human meconium gangliosides. Characterization of a novelI-type ganglioside with the neu-aca2-6gal structure. J Biol Chem 1992;267:11811–7.

[55] Teneberg S, Willemsen P, de Graaf FK, Karlsson KA. Calf small intestine receptors for K99fimbriated enterotoxigenic escherichia coli. FEMS Microbiol Lett 1993;109:107–12.

[56] Wiegandt H. The gangliosides. In: Agranof BW, Aprison MH, editors. Advances in Neurochemistry,vol. 4. New York: Plenum Press, 1982:149–223.

[57] Wiegandt H. Gangliosides. In: Wiegandt H, editor. Glycolipids. Amsterdam: Elsevier, Amsterdam,1985:199–260.

[58] Yu RK, Saito M. Structure and localization of gangliosides. In: Margolis RU, Margolis RK, editors.Neurobiology of Glycoconjugates. New York: Plenum Press, 1989:1–42.


[59] Yuasa H, Scheinberg DA, Houghton AN. Gangliosides of T lymphocytes: evidence for a role in T-cellactivation. Tissue Antigens 1990;36:47–56.

[60] Yuki N, Taki T, Takahashi M, et al. Penner’s serotype 4 of campylobacter jejuni has a lipopolysac-charide that bears a GM1 ganglioside epitope as well as one that bears a GD1a epitope. InfectImmunol 1994;62:2101–3.

Neonatal dietary gangliosides

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